Digest

摘要

Faith in antidepressants seems to be fading. Expectations with regard to efficacy may be higher than the reality of clinical practice write US psychiatrists, reviewing the evidence for augmenting antidepressant therapy with atypical antipsychotics in treatment-resistant depression (Acta Psychiatr Scand 2008;117:253-9). Response rates of 60-70 per cent in clinical trials mask the fact that many people continue to have significant functional impairment; few achieve remission and the STAR*D trial showed that most who do relapse within a year. nAugmentation of antidepressant therapy is therefore an attractive proposition. The potential of atypical antipsychotics appears to lie in their complex effects on serotonin receptors in addition to many other possible actions on dopamine, noradrenaline and NMDA function. nReviewing controlled trials of atypicals in patients for whom at least one adequate trial of antidepressant therapy failed, the authors note that initial experience was encouraging. For example, adding olanzapine after failure of fluoxetine achieved remission (defined as HAM-D score 7) in 60 per cent of patients compared with 20 per cent who continued fluoxetine and 25 per cent taking olanzapine alone. Subsequent larger trials had mixed results, partly due to methodological problems. Experience with risperidone followed a similar pattern. nThere has been greater consistency with augmentation using quetiapine, in combination with SSRIs or SNRIs, and favourable but less robust evidence for ziprasidone. Evidence for aripiprazole is limited to small, short-term trials. nThe authors conclude there is adequate evidence only for augmentation with olanzapine (despite the inconsistency of the trials) and quetiapine. They caution that the adverse effects of atypicals pose such problems that augmentation is not an option early in the course of treatment. More trials are needed to clarify their role. nnAromatherapy for behaviour problems in dementia nThe adverse effects of atypical antipsychotics in patients with dementia - which include an increased risk of stroke in the elderly - have greatly limited their role in the management of behaviour problems. One alternative proposed by NICE is aromatherapy, prompting UK researchers to assess the supporting evidence (Int J Geriatr Psychiatry 2008; 23:337-46). nTheir literature search identified 11 prospective randomised trials of aromatherapy as a treatment for behavioural and psychological symptoms in a total of 298 patients with dementia. In fact, so few publications met their search criteria that they included in their analysis all the randomised trials they found. nThere were important methodological failings, including lack of statistical power in eight trials (fewer than 25 participants); mixed assessment methods, some of which were qualitative; and inadequate blinding. Lavender was the oil most frequently assessed; others included lemon balm, tea tree and sweet orange, and some used mixtures of several oils. Only one trial involved individualisation of treatment (oils being selected according to the characteristics of the patient) and there was little assessment of adverse effects. Meta-analysis of these trials was not possible. nThe authors conclude that, although aromatherapy is potentially useful for behaviour problems in dementia, standards of weighing risk and benefit are not being applied to aromatherapy in the same way as they are to antipsychotics. While this probably reflects the popular belief that this is a safe intervention, there is no adequate evidence to support such a view. nnNurse supplementary prescribing in an acute unit nSupplementary prescribing - the voluntary partnership between an independent prescribing doctor and a supplementary prescribing nurse - was introduced several years ago but uptake has been limited by organisational barriers, lack of awareness and lack of confidence among clinicians. Initiatives have largely been led by nurses and the impact on psychiatrists has provoked little comment. nThe team at Wrexham Hospital has now described its experience implementing a supplementary prescribing scheme in an acute inpatient setting (Psychiatr Bull 2008;32:136-9). They used a five-step model in which a nurse consultant is responsible for the first 72 hours of care, after which a treatment plan is agreed with a psychiatrist. This incorporates the clinical management plan, the document that formally delegates prescribing authority and sets out guidance for assessment and prescribing. Patient review and ward rounds are the responsibility of the nurse consultant; the psychiatrist provides advice at management review meetings and is on call for urgent consultation. nCare management plans implemented to date include switching antipsychotics, adding hypnotics, anxiolytics or antidepressants, initiating and titrating clozapine and other antipsychotics. Acknowledging the issues of delegation and distributing responsibility is the key to success, say the authors. nnStopping antipsychotics in dementia nDespite concerns about the safety of antipsychotics in people with dementia, some use has persisted. UK specialists recently reported a placebo-controlled trial of discontinuation in 165 patients with severe behaviour disorders associated with Alzheimer's disease to determine whether continued use of antipsychotics was associated with accelerated cognitive decline (DART-AD trial, PLoS Med 2008;5:e76. doi:10.1371/journal.pmed.0050076). nPatients were randomised to switch to placebo or continue treatment for 12 months. Of these, 22 per cent did not begin their randomised treatment and a further 26 patients were lost to follow-up, leaving 102 for analysis. An additional 47 did not complete 12 months' follow up, nearly half of whom died. nAt six months, the Severe Impairment Battery (SIB) score deteriorated in both groups with no difference between them. There was also no difference in overall neuropsychiatric symptoms scores in continued treatment and placebo groups though there was a trend for a beneficial effect of antipsychotics in patients with worse symptoms, and a trend favouring placebo in assessment of parkinsonism. There was a significant difference between placebo and continued treatment in verbal fluency assessment, favouring placebo. Only 55 patients remained in the study at 12 months and, although SIB score favoured placebo, the difference was not statistically significant. However, there was a significant difference in neuropsychiatric symptom score at 12 months, favouring continued treatment, with some evidence to suggest patients with more severe symptoms benefit most. nFor most patients, stopping an antipsychotic makes no difference and may even improve functional and cognitive status, the authors conclude. The possible benefits of continuing treatment for patients with severe neuropsychiatric symptoms must be weighed against the risks of adverse effects. nTwo new studies have investigated the effects of olanzapine and quetiapine on cognitive function in patients with dementia and behavioural disorders. nIn a six-week placebo-controlled trial of 40 patients with Alzheimer's disease, quetiapine did not improve psychotic symptoms and did not affect scores of cognitive or motor function (Int J Ger Psychiatr 2008;23:393-400). A pooled analysis of three placebo-controlled trials of olanzapine found no significant effect on cognitive function overall compared with placebo; the authors acknowledged that negative effects could not be excluded in some patients with worse cognitive function or whose behavioural problems remain uncontrolled (Int J Geriatr Psychiatry 2008;23:364-9). nnAutomating MS treatment decisions nComputerised assessment of interferon beta treatment can predict clinical outcomes for patients with relapsing-remitting multiple sclerosis, say Spanish investigators (BMC Neurology 2008;8:3. doi:10.1186/1471-2377-8-3). nThey developed software to implement the recommendations of the Canadian Multiple Sclerosis Working Group for assessing patients and optimising treatment. The software utilises clinical assessments of attacks, progression and MRI to formulate a risk report stating whether treatment should continue or change. Such an approach would avoid subjective assessment, they suggest. nUsing a retrospective sample of 55 patients initially treated with interferon beta 1a 30mg per week, and subsequent clinical outcomes as a comparator, the software had a sensitivity of 74 per cent, a specificity of 84 per cent and a positive predictive value of 77 per cent for treatment optimisation for up to five years based on the first year's outcomes. It performed better at predicting progression than relapse. nnKinetics explain poor sumatriptan response nOral sumatriptan does not relieve headache in almost one-third of patients with migraine, Italian pharmacologists say, prompting them to compare the drug's pharmacokinetics in responders and non-responders (Eur J Clin Pharmacol 2008;64:489-95). nDefining responders as those showing an improvement from moderate/severe to none/mild headache within two hours in four of five attacks treated with a rapidly disintegrating tablet, the pharmacokinetic characteristics of sumatriptan were compared after oral (100mg) and subcutaneous (6mg) administration in responders and non-responders. nCompared with responders, the absorption of sumatriptan was delayed in non-responders: whereas peak levels occurred after 90 minutes in responders, they were delayed until 240 minutes (but not diminished) in non-responders. Systemic exposure to sumatriptan during the first two hours was therefore significantly greater among responders, which is most important for rapid onset and antimigraine efficacy. By contrast, there were no differences between the groups after subcutaneous administration, with peak levels of sumatriptan occurring after 5-15 minutes. nnLittle evidence of value of mirtazapine for anorexia nervosa nA small retrospective study suggests that mirtazapine has little impact in the treatment of anorexia nervosa (Eur Child Adolesc Psychiatry 2008;doi 10.1007/ s00787-007-0670-8). nCzech specialists compared outcomes in nine adolescent girls with anorexia nervosa (mean age 15 years) who had been treated with mirtazapine (mean dose 22mg daily after four weeks) and nine girls the same age who had received no drug treatment. Both groups received nutritional rehabilitation and psychotherapy. Both groups gained weight; body mass index initially increased more with mirtazapine than among controls but after four weeks the groups were not significantly different. The authors acknowledge the shortcomings of their paper but nonetheless suggest that mirtazapine warrants further study. nnDo volunteers bias early trials? nInvestigators from Portugal suggest that people who volunteer to participate in Phase I clinical trials may bias the reporting of adverse events (Eur J Clin Pharmacol 2008;doi 10.1007/ s00228-008-0468-8). nThey studied 198 healthy volunteers participating in a Phase I trial of new antiepileptic and antiparkinsonian drugs and 117 who had never participated in a trial. The novices were invited to join a Phase I trial that would involve procedures, confinement, residence at the research facility and compensation similar to the requirements for the real trial. Of those who responded, 51 accepted the invitation and 59 refused. nCompared with those who accepted, declining participation was associated with higher scores in trait anxiety, a greater tendency to suffer distress from social interactions but no difference in depression scores. Turning to real trial participants, the study showed that those with lower trait anxiety scores reported fewer adverse events. nParticipants in Phase I trials are self-selected by less anxious and less socially avoidant people who are less likely to report adverse events than a trial population genuinely representative of the community. The authors suggest that assessment of anxiety may be important to assess potential bias. nnFluoxetine prevents relapse in children nFluoxetine is the only SSRI proved effective in the treatment of acute depression in children but little is known about its efficacy in preventing relapse during continuation therapy. nA total of 102 children with an adequate response to 12 weeks' treatment with fluoxetine (approximately 90 per cent in remission) were randomised to placebo or continuing treatment for six months (Am J Psychiatry 2008;165:459-67). When relapse was defined as Children's Depression Rating Scale-Revised (CDRS-R) score 40 with a history of two weeks' clinical deterioration or clinical assessment of deterioration, relapse rates were 69 per cent with placebo and 42 per cent with fluoxetine. By a stricter definition (CDRS-R score 40 only), rates were 48 and 22 per cent respectively. Time to relapse was also significantly shorter with placebo. nnTestosterone, age and depression nLow testosterone levels in older men may be a treatable cause of depression, Australian investigators believe (Arch Gen Psychiatry 2008;65:283-9). nTheir cross-sectional study of 3987 men aged 71-89 years living in the community identified 203 (5 per cent) with depression assessed by the Geriatric Depression Scale. These men differed from the majority in many ways, including greater likelihood of smoking, lower educational attainment, more obesity and physical morbidity, lower scores of cognitive function and more use of antidepressants. nAfter adjustment for these differences and for age, men with the lowest quintiles of total (<10.7nanomol per litre) and free (<0.21nanomol per litre) testosterone levels were significantly more likely to have depression (odds ratios 1.55 and 2.71 respectively). nnBalance of effects with cannabis nDifferent strains of cannabis contain varying proportions of two mutually antagonistic cannabinoids - delta-9 tetrahydrocannabinol (THC), which has psychotomimetic properties, and cannabadiol, which has antipsychotic activity. According to psychopharmacologists in London and Oxford, the balance of the effects of the two cannabinoids may help to explain some of the unwanted effects of smoking cannabis (Br J Psychiatry 2008; 192:306-7). nThey identified 20 individuals with traces only of delta-9 THC in hair samples and 27 with both delta-9 THC and cannabadiol; a control group comprised 85 individuals with no cannabinoids in hair samples, some of whom used recreational drugs but not cannabis. nPsychosis proneness was assessed using the Oxford Liverpool Inventory of Life Experiences. Scores for unusual experiences were significantly higher in the THC only group than in the THC/cannabadiol group or non-users. Scores for introvertive anhedonia were significantly lower in the TCH/cannabadiol group than the THC only group. nDelusional thinking was assessed by Peter's Delusion Inventory. Compared with nonusers, scores were significantly higher in the THC only group and higher, but not significantly so, among the THC/cannabidiol group. nThe authors suggest that strains of cannabis containing both THC and cannabadiol may be associated with a lower risk of delusional thinking and hallucinations. nnAripiprazole approved for bipolar mania nAripiprazole has received European marketing authorisation for the treatment of moderate to severe manic episodes in bipolar I disorder and for the prevention of new manic episodes in patients who experienced predominantly manic episodes and whose manic episodes responded to treatment with the drug. The submission for the new indication was based on data from eight randomised trials involving over 2400 people. nOne of the most important characteristics for long-term treatment with the drug is that it is not sedating, according to Professor Andrea Fagiolini, Associate Professor of the Bipolar Disorder Center at the University of Pittsburgh Medical School in the USA where aripiprazole has been licensed for bipolar disorder since 2004. Professor Andrea Fagiolini said that patients taking aripiprazole do not feel drugged; in other words they do not experience the drowsiness that they may feel when taking other medicines. This characteristic could be important during maintenance treatment when patients who feel well may be put off taking their medicines by side-effects such as drowsiness. Professor Fagiolini was speaking at a satellite symposium sponsored by Bristol Myers Squibb and Otsuka Pharmaceutical Europe. The symposium was held at the Association of European Psychiatrists' 16th European Congress of Psychiatry in Nice, France, in March. Copyright © 2008 Wiley Interface Ltd